ES2830974T3 - New xanthene protective agent - Google Patents

Abstract

A xanthene compound of general Formula (1) ** (See formula) ** wherein Y is -OR17, R17 being a hydrogen atom, an active ester-carbonyl group or an active ester-sulfonyl group, -NHR18, being R18 a hydrogen atom or a linear or branched C1-C6 alkyl group or aralkyl group, an azide, a halogen atom, or a carbonyl oxygen = O; at least one of R1 to R8 is represented by Formula (2); -O-R9-XA (2) and a residue is a hydrogen atom, a halogen atom, a C1-C4 alkyl group or a C1-C4 alkoxy group, wherein R9 is a linear or branched C1-C16 alkylene group ; X is O or CONR19, where R19 is a hydrogen atom or a C1-C4 alkyl group; and A is represented by Formula (3), (4), (5), (6), (7), (8), (9), (10), (11), (12) or (13) ** (See formula) ** wherein R10, R11 and R12, the same or different, are a linear or branched C1-C6 alkyl group or an aryl group optionally including a substituent; R13 is a single bond or a linear or branched C1-C3 alkylene group; and R14, R15 and R16 are a linear or branched C1-C3 alkylene group.

Description

DESCRIPTION

New xanthene protective agent

Field of the invention

The present invention relates to a new xanthene compound useful as a protective agent to protect, for example, a carboxy group, a hydroxy group, a diol group, an amino group, an amide group or a mercapto group. Background of the invention

In peptide synthesis or multi-compound synthesis, some reactions require protection of functional groups such as a carboxy group, a hydroxy group, a diol group, an amino group, an amide group, and a mercapto group. A protecting group for those functional groups is required to be able to protect the functional groups by a simple method and be removed from the functional groups under mild conditions. Benzyl ester (Bn) and tert-butyl ester are known as examples of a protecting group for a carboxy group. According to recent reports (Patent Bibliography 1 and 2), benzyl alcohol compounds and diphenylmethane compounds have been found to be useful as protecting groups. Patent Bibliography 3 refers to compounds useful in peptide synthesis as blocking or protecting groups for reactive groups. Citation List: Patent Bibliography

Patent Bibliography 1: WO 2012/029794 A

Patent Bibliography 2: WO 2010/113939 A

Patent Bibliography 3: WO 91/08190

Summary of the invention

Technical problem

However, deposition is a disadvantage that is commonly found in a compound that includes a functional group protected by a protecting group in the related art. In particular, in the synthesis of peptides, such a compound is insoluble in an organic solvent, which often causes difficulty in the separation and purification of the compound after the reaction. Difficulty of separation and purification is a major problem in peptide synthesis where a condensation reaction is carried out continuously.

Consequently, an object of the present invention is to improve the solubility, in an organic solvent, of a compound that includes a protected functional group, thereby offering a protective group that facilitates the separation and purification of the compound after the reaction, without solidify or insolubilize the compound.

Solution to the problem

As a result of extensive studies on xanthene compound substituents, the present inventors have developed a compound having a trialkylsilyloxy substituent at the terminus of an oxyalkylene group whereby the substituent is connected to a benzene ring of a xanthene compound. The present inventors have found that a compound including a functional group protected by the xanthene compound is hardly deposited in an organic solvent and is easily separated and purified by liquid-liquid phase separation, and that the compound is useful as a protective agent, whereby the invention is completed.

In other words, the present invention is to provide the following [1] to [12].

[1] A xanthene compound of general Formula (1)

(where Y is -OR17 (R17 is a hydrogen atom or an active ester protecting group as defined in claim 1), -NHR18 (R18 is a hydrogen atom or a linear or branched C1-C6 alkyl group or aralkyl group), an azide, a halogen atom or a carbonyl oxygen = O;

at least one of R1 to R8 is represented by Formula (2);

-O-R9-X-A (2)

and a residue is a hydrogen atom, a halogen atom, a C1-C4 alkyl group or a Ci-C4 alkoxy group,

wherein R9 is a linear or branched C1-C16 alkylene group;

X is O or CONR19 (R19 is a hydrogen atom or a C1-C4 alkyl group); Y

A is represented by the Formula (3), (4), (5), (6), (7), (8), (9), (10), (11), (12) or (13)

(wherein R 10, R 11 and R 12, the same or different, are a linear or branched C1-C6 alkyl group or an aryl group optionally including a substituent;

R13 is a single bond or a linear or branched C1-C3 alkylene group; Y

R14, R15 and R16 are a linear or branched C1-C3 alkylene group)).

[2] The xanthene compound according to [1], wherein Y is -OR17 (R17 is a hydrogen atom or an active ester protecting group as defined in claim 2), -NHR18 (R18 is an atom of hydrogen or a linear or branched C1-C6 alkyl group or aralkyl group), an azide or a halogen atom.

[3] The xanthene compound according to [1], wherein Y is -OR17 (R17 is a hydrogen atom or an active ester protecting group as defined in claim 3) or -NHR18 (R18 is a hydrogen or a linear or branched C1-C6 alkyl group or aralkyl group).

[4] The xanthene compound according to [1], wherein Y is -OR17 (R17 is a hydrogen atom), -NHR18 (R18 is a hydrogen atom) or a carbonyl oxygen = O.

[5] The xanthene compound according to [1], wherein Y is -OR17 (R17 is a hydrogen atom), or -NHR18 (R18 is a hydrogen atom).

[6] The xanthene compound according to any one of [1] to [5], wherein at least one of R1 to R8 is a group represented by Formula (2), and a residue is a hydrogen atom, a C1-C4 alkyl group or C1-C4 alkoxy group.

[7] The xanthene compound according to any one of [1] to [6], wherein R9 is a linear or branched C2-C16 alkylene group.

[8] The xanthene compound according to any one of [1] to [7], wherein R9 is a linear or branched C6-C16 alkylene group.

[9] The xanthene compound according to any one of [1] to [8], wherein R13 is a single bond or a methylene group, and R14, R15 and R16 are a methylene group.

[10] A protective agent for protecting a carboxy group, a hydroxy group, a diol group, an amino group, an amide group or a mercapto group, wherein the protective agent contains the xanthene compound according to any one of [1 ] to [9].

[11] A method for producing a compound with a protective agent to protect a carboxy group, a hydroxy group, a diol group, an amino group, an amide group, or a mercapto group, wherein the protective agent contains the xanthene compound of according to any one of [1] to [9].

[12] A method for producing a peptide with a protective agent to protect a carboxy group, a hydroxy group, a diol group, an amino group, an amide group, or a mercapto group, wherein the protective agent contains the xanthene compound of according to any one of [1] to [9].

Effects of the invention

A compound including a functional group protected by the xanthene compound (1) of the present invention is easily liquefied and has a higher solubility in a solvent. Therefore, the compound after a condensation reaction is easily separated and purified by liquid-liquid phase separation.

When the insolubilization and fixation of raw materials or intermediates are obstacles to the production of various chemicals, such as medicines and agricultural chemicals, the binding of the xanthene compound (1) of the present invention to the raw materials or intermediates improves the solubility. of raw materials or intermediates. compounds, which leads to the solution of the above problems.

Brief description of the drawings

Fig. 1 shows the results of the measurement of solubility in cyclopentyl methyl ether (CPME).

Description of the achievements

In a xanthene compound of general formula (1) according to the present invention, at least one of R1 to R8 has a structure represented by Formula (2). With such a structure, a compound protected by this xanthene compound (1) is easily liquefied and has remarkably improved solubility in a solvent.

17 17 1 q In general Formula (1), Y is -OR (R is a hydrogen atom or an active ester protecting group), -NHR (R18 is a hydrogen atom or a linear C1-C6 alkyl group or branched or aralkyl group), an azide, a halogen atom or a carbonyl oxygen = O. Examples of the halogen atom include a fluorine atom, a bromine atom, a chlorine atom and an iodine atom.

The active ester protecting group is an active ester-carbonyl group or an active ester-sulfonyl group. Examples of the active ester-carbonyl group include carbonyloxysuccinimide, an alkoxycarbonyl group, an aryloxycarbonyl group, and an aralkyloxycarbonyl group, and a preferable example is carbonyloxysuccinimide.

Examples of the active ester sulfonyl group include an alkylsulfonyl group and an arylsulfonyl group, and preferable examples are a C1-C6 alkylsulfonyl group and a p-toluenesulfonyl group.

^{7 1 fi 1 fi} Y is preferably -OR ^{1 7 1} (R is a hydrogen atom or an active ester protecting group), -NHR (R is a hydrogen atom or a linear or branched C1-C6 alkyl group or group aralkyl), an azide or a halogen atom.

17 17 1 q Most preferably, Y is -OR (R is a hydrogen atom or an active ester protecting group), or -NHR (R18 is a hydrogen atom or a linear or branched C1-C6 alkyl group or aralkyl group ).

^{1 7 1 fi 1 fi} Even more preferably, Y is -OR (R ^{1 7} is a hydrogen atom) or -NHR (R is a hydrogen atom). In the xanthene compound of the present invention, at least one of R1 to R8 is a group represented by Formula (2) and it is preferred that one or two of them are groups represented by Formula (2).

A residue is a hydrogen atom, a halogen atom, a C1-C4 alkyl group or a C1-C4 alkoxy group. Examples of the residual halogen atom represented by R1 to R8 include a fluorine atom, a chlorine atom and a bromine atom. Among these examples, a fluorine atom and a chlorine atom are preferred. Examples of the residual C1-C4 alkoxy group include methoxy groups, ethoxy groups, n-propyloxy groups, isopropyloxy groups, and n-butyloxy groups. Among these examples, methoxy groups are preferred. Examples of the C1-C4 alkyl group include methyl groups, ethyl groups, n-propyl groups, isopropyl groups, and n-butyl groups. Among these examples, methyl groups are preferred.

R9 is a linear or branched C1-C16 alkylene group. From the viewpoint of improving the solubility, in a solvent, of the compound to which the xanthene compound (1) is bound, the number of carbon atoms of the alkylene group is preferably 2 or more, more preferably 6 or more, even more preferably 8 or more, and preferably 16 or less, more preferably 14 or less, even more preferably 12 or less.

The alkylene group is preferably a linear or branched C2-C16 alkylene group, more preferably a linear or branched C6-C16 alkylene group, even more preferably a linear or branched C8-C14 alkylene group and even more preferably, a C8 alkylene group -C12 linear or branched. Specific examples of the alkylene group include methylene groups, ethylene groups, trimethylene groups, tetramethylene groups, pentamethylene groups, hexamethylene groups, heptamethylene groups, octamethylene groups, nanomethylene groups, decamethylene groups, undecamethylene groups, dodecamethylene groups, and tetradecamethylene groups.

X is O or CONR19.

Herein, R19 is a hydrogen atom or a C1-C4 alkyl group and is preferably a hydrogen atom.

A is a group represented by Formula (3), (4), (5), (6), (7), (8), (9), (10), (11), (12) or (13) . R10, R11 and R12, the same or different, are a linear or branched C1-C6 alkyl group or an aryl group optionally including a substituent. Examples of the C1-C6 alkyl group include methyl groups, ethyl groups, n-propyl groups, isopropyl groups, n-butyl groups, isobutyl groups, sec-butyl groups, tert-butyl groups, n-pentyl groups, and n-hexyl groups. . Among these examples, a C1-C4 alkyl group is preferable, and methyl, tert-butyl groups and isopropyl groups are more preferable.

Examples of the aryl group that may have a substituent include a C6-C10 aryl group, and specific examples thereof include a phenyl group and a naphthyl group in which a C1-C3 alkyl group may be substituted by another group. Among these examples, a phenyl group is more preferred.

R13 is a single bond or a linear or branched C1-C3 alkylene group. Examples of the linear or branched C1-C3 alkylene group include methylene groups, ethylene groups, trimethylene groups, and propylene groups. Among these examples, a single bond is particularly preferred.

R, R and R are a linear or branched C1-C3 alkylene group. Examples of the linear or branched C1-C3 alkylene group include methylene groups, ethylene groups, trimethylene groups, and propylene groups, and methylene groups are particularly preferred.

More preferably, the compound is such that, in general Formula (1), Y is -OR17 (R17 is a hydrogen atom) or -NHR18 (R18 is a hydrogen atom); at least one of R1 to R8, preferably one or two of R1 to R8 are represented by Formula (2), and a residue is a hydrogen atom, a C1-C4 alkyl group or a C1-C4 alkoxy group; R9 is a linear or branched C2-C16 alkylene group; R13 is a single bond or a methylene group; and R14, R15 and R16 are a methylene group.

Even more preferably, the compound is such that, in Formula (2), R9 is a linear or branched C6-C16 alkyl group; X is O or CONH; A is a group represented by Formula (3) or (13); R10, R11 and R12, the same or different, are a C1-C4 alkyl group; R13 is a single bond; and R14, R15 and R16 are a methylene group.

The following structure is preferable as a structure in which Y and R1 to R8 in Formula (1) are substituted by other groups.

(where R3b and R7b are hydrogen atoms, a C1-C4 alkyl group or a C1-C4 alkoxy group; and Y, A, X and R9 are the same as above).

Examples of the xanthene compound (1) of the present invention include the following (a) to (e).

(a) TIPS2-PP protective agent

(where Y is ^{1 7 1 7 1 fi 1 fi a} -OR (R is a hydrogen atom) or -NHR (R is a hydrogen atom), R is a hydrogen atom, a C1-C4 alkyl group, or a C1-C4 alkoxy group.)

(a) TIPS3-P protective agent

(where Y and Ra are the same as in (a)).

(c) TIPS4-PP protective agent

(e) TBDPS2-PP protective agent

(where Y and Ra are the same as in (a)).

The xanthene compound (1) of the present invention is produced, for example, according to the following reaction formula.

(where Hal is a halogen atom; at least one of R1a to R8a is a hydroxy group, and a residue is a hydrogen atom, a halogen atom, a C1-C4 alkyl group or a C1-C4 alkoxy group; B is an amino acid derivative that includes a mercapto group; Z is a compound that includes a -CONH- group; and R1 to R8, X and A are the same as above).

A silyloxylated alkyl halide (14) is reacted with a xanthene compound (15) to produce a silyloxylated xanthene compound (16). Next, a carbonyl group of the silyloxylated xanthene compound (16) is converted to a hydroxy group and reacted with a compound that includes a -CONH2 group to produce a compound (17). Next, a protecting group of compound (17) is deprotected to produce compound (1b). Furthermore, a xanthene compound (1a) that includes a hydroxy group is reacted with an amino acid that includes a mercapto group or with an amino acid derivative that includes a mercapto group to produce a compound (18).

The silyloxylated alkyl halide (14) which is a raw material herein is produced, for example, by reacting a halogenated alcohol with a silylating agent in the presence of a base. An example of the halogen atom in compound (14) includes a bromine atom.

Examples of the silylating agent used in the above reaction include triisopropylsilyl chloride (TIPSCl), triisopropylsilyl bromide, triisopropylsilyl iodide, methanesulfonyltriisopropylsilyl, trifluoromethanesulfonylisopropylsilyl, ptoluenesulfonyltriisopropylsilyl.

Examples of the base include organic bases. such as TEA, DIPEA, DBU, diazabicyclonone (DBN), DABCO, imidazole, N-methylimidazole, N, N-dimethylaniline, pyridine, 2,6-lutidine, DMAP, LDA, NaOAc, MeONa, MeOK, lithium hexamethyldisilazide (LHMDS ) and sodium bis (trimethylsilyl) amide (NaHMDS); and inorganic bases, such as Na2COa, NaHCOa, NaH, NaNH2, K2CO3, and Cs2COa.

Examples of the solvent include hydrocarbons, such as hexane and heptane; ethers, such as diethyl ether, diisopropyl ether, cyclopentyl methyl ether (CPME), tetrahydrofuran, and dioxane; nitriles, such as acetonitrile; amides, such as dimethylformamide (DMF), dimethylacetamide, and hexamethylphosphoramide; sulfoxides, such as dimethylsulfoxide; lactams, such as N-methylpyrrolidone; hydrogen halides, such as chloroform and dichloromethane; aromatic hydrocarbons, such as toluene and xylene; and mixed solvents of these examples. The reaction can be carried out, for example, at 0 ° C to 100 ° C for 1 hour to 24 hours.

The reaction of the silyloxylated alkyl halide (14) and the xanthene compound (15) is preferably carried out in the presence of a base.

Examples of the base used in the above reaction include organic bases, such as TEA, DIPEA, DBU, DBN, DABCO, imidazole, N-methylimidazole, N, N-dimethylaniline, pyridine, 2,6-lutidine, DMAP, LDA, NaOAc , MeONa, MeOK, lithium hexamethyldisilazide (LHMDS) and sodium bis (trimethylsilyl) amide (NaHMDS); and inorganic bases, such as Na2CO3, NaHCO3, NaH, K2CO3, and Cs2CO3.

Examples of the solvent include hydrocarbons, such as hexane and heptane; ethers, such as diethyl ether, diisopropyl ether, CPME, tetrahydrofuran, and dioxane; nitriles, such as acetonitrile; amides, such as DMF, dimethylacetamide, and hexamethylphosphoramide; sulfoxides, such as dimethylsulfoxide; lactams, such as N-methylpyrrolidone; hydrogen halides, such as chloroform and dichloromethane; aromatic hydrocarbons, such as toluene and xylene; and mixed solvents of these examples.

The reaction can be carried out, for example, at 40 ° C to 150 ° C for 1 hour to 24 hours.

With respect to a method for converting a carbonyl group in the compound of Formula (16) to a hydroxycarbonyl group, an example of the method includes reduction with a reducing agent.

Examples of the reducing agent include lithium borohydride, sodium borohydride, lithium aluminum hydride, and aluminum hydride. Examples of the solvent include hydrocarbons, such as hexane and heptane; alcohols, such as methanol and ethanol; ethers, such as diethyl ether, diisopropyl ether, CPME, tetrahydrofuran, and dioxane; aromatic hydrocarbons, such as toluene and xylene; and mixed solvents of these examples. The reaction is preferably carried out, for example, at 0 ° C to 90 ° C for 1 hour to 120 hours.

With respect to the reaction between the compound of formula (1a) and the compound that includes a -CONH2 group, the compound of Formula (1a) is preferably reacted with the compound that includes a -CONH2 group in an acid catalyst.

Examples of the compound that include a -CONH2 group include Fmoc-NH2, ethyl carbamate, isopropyl carbamate, AcNH2, HCONH2, Cbz-NH2, CF3CONH2, and Fmoc-amino acid-NH2. Examples of the acid catalyst include acids, such as trifluoromethanesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, acetic acid, hydrochloric acid, and sulfuric acid. Examples of the solvent include hydrocarbons, such as hexane and heptane; ethers, such as diethyl ether, diisopropyl ether, CPME, tetrahydrofuran, and dioxane; aromatic hydrocarbons, such as toluene and xylene; hydrogen halides, such as chloroform and dichloromethane; and mixed solvents of these examples. The reaction can be carried out, for example, at 20 ° C to 150 ° C for 0.5 hours to 48 hours.

To obtain the compound (1b) from the compound of formula (17), it is preferable to treat the compound (17) with a base.

Examples of the base include bases, such as diethylamine, piperidine, dimethylamine, DBU, morpholine, sodium hydroxide, and potassium hydroxide. Examples of the solvent include hydrocarbons, such as hexane and heptane; ethers, such as diethyl ether, diisopropyl ether, CPME, tetrahydrofuran, and dioxane; aromatic hydrocarbons, such as toluene and xylene; hydrogen halides, such as chloroform and dichloromethane; alcohols, such as methanol, ethanol, and isopropyl alcohol; and mixed solvents of these examples. The reaction can be carried out, for example, at 0 ° C to 150 ° C for 0.5 hours to 48 hours.

With respect to the reaction between the compound of formula (1a) and the amino acid derivative that includes a mercapto group, the compound of formula (1a) is preferably reacted with an amino acid that includes a mercapto group or with the amino acid derivative that includes a mercapto. group under an acid catalyst.

Examples of the amino acid that includes a mercapto group include cysteine, homocysteine, mercaptonorvaline, and mercaptonorleucine. Examples of the amino acid derivative that includes a mercapto group include a compound in which an N-terminal of these examples of the amino acid is N-methylated; a compound in which an N-terminal of these examples of the amino acid is protected by, for example, a benzyloxycarbonyl group (Cbz or Z), a fluorenylmethoxycarbonyl group (Fmoc), an acetyl group (Ac), a benzyl group, an allyl group , an allyloxycarbonyl group (Aloc), a 2-nitrobenzenesulfonyl group (Ns), a 2,4-dinitrobenzenesulfonyl group (DNs) and a 4-nitrobenzenesulfonyl group (Nos); a compound in which a C terminal of these examples of the amino acid is protected by, for example, an amide group, a methyl ester group, an ethyl ester group, a tert-butyl ester group, a benzyl ester group and an allyl ester group; a compound in which both the N and C terminals are protected by a protecting group like the previous examples; and D-amino acid compounds corresponding to these examples.

Examples of the acid catalyst include acids, such as trifluoromethanesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, acetic acid, hydrochloric acid, and sulfuric acid. Examples of the solvent include hydrocarbons, such as hexane and heptane; ethers, such as diethyl ether, diisopropyl ether, CPME, tetrahydrofuran, and dioxane; aromatic hydrocarbons, such as toluene and xylene; hydrogen halides, such as chloroform and dichloromethane; and mixed solvents of these examples. The reaction can be carried out, for example, at 20 ° C to 150 ° C for 0.5 hours to 24 hours.

The xanthene compound (1) of the present invention can be used as a protective agent for a functional group such as a carboxy group, a hydroxy group, a diol group, an amino group, an amide group, and a mercapto group. A compound in which a carboxy group, a hydroxy group, a diol group, an amino group, an amide group, or a mercapto group is protected by the xanthene compound (1) of the present invention is excellent in liquefaction property and solubility in a solvent. Therefore, the compound in which the functional group is protected by the xanthene compound (1) of the present invention as a protective agent is easily dissolved in an organic solvent and easily separated and purified by, for example, phase separation. liquid-liquid. Furthermore, the protecting group used in the compound of the present invention is easily removed by, for example, acid or catalytic reduction.

The compound protected by the xanthene compound (1) of the present invention can be a compound that includes a carboxy group, a hydroxy group, a diol group, an amino group, an amide group or a mercapto group. Examples of such a compound include amino acids, peptides, saccharide compounds, proteins, nucleotides, various other pharmaceutical and agrochemical compounds, and various other polymers and dendrimers.

An example of a method for synthesizing a peptide with the xanthene compound (1) of the present invention as a protective agent includes a method involving the following steps (1) to (4). This peptide synthesis method is particularly favorable in the industrial field since a protected peptide obtained in each step is separable by liquid-liquid phase separation.

If necessary, in an intermediate stage, an intermediate compound can be temporarily isolated from solution and purified, and then subjected to the next stage, which makes the method more favorable in the industrial field.

(1) The xanthene compound (1) of the present invention is condensed with a C-terminal carboxy group of an N-protected amino acid or an N-protected peptide in a soluble solvent to produce a N- and C-protected amino acid or an N- and C-protected peptide in which the C-terminus is protected by the xanthene compound (1) of the present invention. Alternatively, the xanthene compound (1) of the present invention is reacted with a C-terminal amide group of an N-protected amino acid or an N-protected peptide in a soluble solvent to produce an N- and C-protected amino acid. or an N and C protected peptide in which the C-terminus is protected by the xanthene compound (1) of the present invention.

(2) With respect to the N and C-protected amino acid or the N and C-protected peptide obtained herein, an N-terminal protecting group is removed to produce a C-protected amino acid or a C-protected peptide.

(3) With respect to the C-protected amino acid or the C-protected peptide obtained herein, the N terminal is fused with an N-protected amino acid or with an N-protected peptide to produce an N and C-protected peptide.

(4) With respect to the N- and C-protected peptide obtained herein, the protecting groups are removed from the N-terminal and the C-terminal to produce a desired peptide.

Examples of the soluble solvent include hydrocarbons, such as hexane and heptane; ethers, such as diethyl ether, diisopropyl ether, CPME, tetrahydrofuran, 2-methyltetrahydrofuran, 4-methyltetrahydropyran, dioxane, and methyl tert-butyl ether; esters, such as ethyl acetate, butyl acetate, isopropyl acetate, and isobutyl acetate; hydrogen halides, such as chloroform and dichloromethane; aromatic hydrocarbons, such as toluene and xylene; and mixed solvents of these examples. These examples of the soluble solvent can be mixed with a solvent, for example nitriles, such as acetonitrile; amides, such as DMF, dimethylacetamide, and hexamethylphosphoramide; sulfoxides, such as dimethylsulfoxide; and lactams, such as N-methylpyrrolidone.

Examples of a condensation reagent include COMU, HATU, HBTU, HCTU, TATU, TBTU, TCTU, TOTU, TDBTU, DEPBT, WSCI, WCSI / HCl, DCC, DIC, CDI, PyAop, PyBop, T3P, and DMT-MM.

Examples of condensation aid include Oxyma, HOAt, HOBt, HOOBt, HOCt, HOSu, HONb, and HOPht.

Examples of a base used in a condensation reaction include DIPEA, N-methylmorpholine, 2,4,6-trimethylpyridine, and DMAP.

The condensation reaction can be carried out, for example, at 0 ° C to 40 ° C for 10 minutes to 24 hours. Examples of a scavenger for the N-terminal protecting group and the C-terminal protecting group include bases, such as diethylamine, piperidine, dimethylamine, DBU, DABCO, triethylamine, morpholine, sodium carbonate, sodium tert-butoxide, potassium tert-butoxide; mixtures of these examples; acids, such as acetic acid, formic acid, hydrochloric acid, sulfuric acid, trichloroacetic acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, and hexafluoroisopropanol; and mixtures of these examples.

The N-terminal protecting group can be removed, for example, at 0 ° C to 40 ° C for 5 minutes to 24 hours.

The C-terminal protecting group can be removed, for example, at 0 ° C to 40 ° C for 30 minutes to 24 hours.

[Example]

The present invention will now be described in detail with reference to Examples, but the present invention is not limited to Examples in any way.

Example 1

Synthesis of TIPS2-Xtn-OH

(Hereinafter, Br- (CH2) ii-OTIPS, TIPS2-Xtn-C = O and TIPS2-Xtn-OH represent the structures in the drawing).

Example (1-a)

8.10 g (19.9 mmol) of Br- (CH2) ii-OTIPS, 2.02 g (8.8 mmol) of 3,6-dihydroxyxanthone and 4.39 g (31.8 mmol) of potassium carbonate they were suspended in 58.9 ml of DMF, heated to 85 ° C and stirred for 2 hours. The reaction solution was filtered and the filtration residue was washed with 124 ml of heptane. The filtrate was separated to obtain a layer of heptane. 59 ml of heptane was added to the resulting heptane layer, and the heptane layer was separated and washed with 59 ml of DMF. The heptane layer was separated and washed with the heptane and DMF once more. To the resulting heptane layer, 59 ml of heptane was added, and the heptane layer was washed once with 59 ml of 1N hydrochloric acid, once with 59 ml of a 5% aqueous hydrogen carbonate solution, and twice with 59 ml of water. 59 ml was added to the resulting heptane layer, and the heptane layer was separated and washed once with 59 ml of DMF and twice with 59 ml of acetonitrile. The heptane layer was concentrated under reduced pressure, and a resulting residue was purified by silica gel column chromatography (heptane: ethyl acetate = 70: 1 ^ 0: 100) to provide 7.85 g of TIPS2-Xtn- C = O.

1H NMR (40OMHz, CDCla) 8 1.02-1.08 (m, 42H), 1.24-1.41 (m, 24H), 1.43-1.58 (m, 8H), 1.77 -1.88 (m, 4H), 3.67 (t, 4H), 4.06 (t, 4H), 6.83 (d, 2H), 6.91 (dd, 2H), 8.22 ( d, 2H) 13C NMR (100 MHz, CDCla) 812.2 (6C), 18.2 (12C), 26.0 (2C), 26.1 (2C), 29.2 29.8 (12C), 33.2 (2C), 63.6 (2C), 68.8 (2C), 100.8 (2C), 113.4 (2C), 11 5.8 (2C), 128.2 (2C), 158.2 (2C), 164.4 (2C), 175.7

Example (1-b)

In a mixed solution of 2.3 ml of THF (anhydrous) and 0.45 ml of methanol, 0.30 g (0.34 mmol) of TIPS2-Xtn-C = O were dissolved and 39 mg (1, 02 mmol) of sodium borohydride to the mixed solution. The solution was heated to 55 ° C and stirred for 1 hour 40 minutes. To the solution, 39 mg (1.02 mmol) of sodium borohydride and 0.62 ml of methanol were added and the solution was stirred at 55 ° C for 30 minutes. Furthermore, 78 mg (2.04 mmol) of sodium borohydride was added to the solution and the solution was stirred at 55 ° C for 30 minutes. Furthermore, 39 mg (1.02 mmol) of sodium borohydride and 0.40 ml of methanol were added to the solution, and the solution was stirred at 55 ° C for 30 minutes. To the solution, 1.2 ml of acetone and 7.5 ml of CPME were added, and the solution was washed once with 2.3 ml of water, once with 2.3 ml of a 5% aqueous solution of sodium hydrogen carbonate and twice with 2.3 ml of water. An organic layer was concentrated under reduced pressure. A resulting residue was dissolved in 7.5 ml of heptane, separated and washed with 3.8 ml of DMF. To a resulting heptane layer, 3.8 ml of heptane was added, and the heptane layer was separated and washed with 3.8 ml of acetonitrile. The heptane layer was separated and washed with the heptane and acetonitrile once more, and then, the heptane layer was concentrated under reduced pressure to provide 0.32 g of TIPS2-Xtn-OH.

1H NMR (400 MHz, Benzene ^) 81.12-1.16 (m, 42H) 1.24-1.49 (m, 28H), 1.57-1.68 (m, 9H), 3.65 -3.72 (m, 8H), 5.57 (d, 1H), 6.77 (dd, 2H), 6.86 (d, 2H), 7.40 (d, 2H) 13 C NMR (100 MHz , Benzene ^) 812.8 (6C), 18.7 (12C), 26.7 (2C), 26.8 (2C), 29.8-30.5 (12C), 33.9 (2C), 63.3, 64.1 (2C), 68.6 (2C), 102.0 (2C), 111.9 (2C), 116.8 (2C), 131.5 (2C), 152.5 (2C ), 160.9 (2C)

Example 2

Synthesis of TIPS2-Xtn-NH2

(Hereinafter TIPS2-Xtn-NHFmoc and TIPS2-Xtn-NH2 represent the structures in the drawing).

Example (2-a)

In a mixed solution of 180 ml of THF (anhydrous) and 18 ml of methanol, 21.8 g (24.8 mmol) of TIPS2-Xtn-C = O were dissolved and 7.5 g (198 mmol) of sodium borohydride to the mixed solution. The solution was heated to 35 ° C and stirred for 10 minutes. Furthermore, 18 ml of methanol was added and the solution was stirred at 35 ° C for 1 hour. Furthermore, 3.7 mg (99.0 mmol) of sodium borohydride and 18 ml of methanol were added to the solution and the solution was stirred at 35 ° C for 20 hours and 30 minutes. To the solution, 446 ml of acetone was added, and the reaction solution was concentrated under reduced pressure. A resulting residue was dissolved in 540 ml of toluene and washed 4 times with 360 ml of a 5% aqueous sodium hydrogencarbonate solution. A resulting organic layer was diluted with 18 ml of toluene and 153 g of anhydrous sodium sulfate was added to the organic layer. The organic layer was thoroughly stirred and then filtered. The filtration residue was washed with 90 ml of toluene to provide a toluene solution containing TIPS2-Xtn-OH.

Example (2-b)

To the toluene solution obtained in the previous step, 7.11 g (29.7 mmol) of Fmoc-NH2 and 82.5 ml of acetic acid were added, and the toluene solution was heated to 50 ° C and stirred for 30 minutes. After cooling the reaction solution to 5 ° C, 194 ml of toluene was added to the solution, and the solution was washed three times with 648 ml of a 5% aqueous solution of sodium hydrogen carbonate and twice with 648 ml of water. . An organic layer was concentrated under reduced pressure to provide a mixture containing TIPS2-Xtn-NHFmoc.

Example (2-c)

The mixture obtained in the previous step was dissolved in 248 ml of THF and 13.3 ml (89.1 mmol) of DBU was added to the mixture. Then the solution was stirred at room temperature for 30 minutes. The solution was cooled to 5 ° C, the reaction was quenched with 59.4 ml of 1N hydrochloric acid, and the solution was concentrated under reduced pressure. A resulting residue was dissolved in 500 ml of heptane and the residue was washed five times with 500 ml of acetonitrile. A layer of heptane was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (heptane: ethyl acetate: triethylamine = 18.75: 1.25: 1 ^ 0: 19: 1) to provide 8.86 g of TIPS2-Xtn-NH2.

1H NMR (400 MHz, Benzene-da) 8 1.12-1.16 (m, 42H), 1.24-1.40 (m, 24H), 1.40-1.50 (m, 4H), 1.56-1.68 (m, 10H), 3.65-3.74 (m, 8H), 4.76 (s, 1H), 6.78 (dd, 2H), 6.86 (d, 2H), 7.25 (d, 2H) 13C NMR (100 MHz, Benzene ^) 812.8 (6C), 18.7 (12C), 26.7 (2C), 26.8 (2C), 30, 0-30.5 (12C), 33.9 (2C), 46.8, 64.1 (2C), 68.5 (2C), 102.1 (2C), 111.6 (2C), 119 .0 (2C), 130.6 (2C), 152.6 (2C), 160.3 (2C)

Example 3

Synthesis of TIPS2-Xtn-OH (C8)

(Hereinafter Br- (CH2) 8-OTIPS, TIPS2-Xtn-C = O (C8) and TIPS2-Xtn-OH (C8) represent the structures in the drawing).

Example (3-a)

1.49 g (4.07 mmol) of Br- (CH2) 8-OTIPS, 0.41 g (1.81 mmol) of 3,6-dihydroxyxanthone and 0.90 g (6.52 mmol) of potassium carbonate they were suspended in 12.1 ml of DMF, heated to 85 ° C and stirred for 2 hours and 30 minutes. The reaction solution was filtered and the filtration residue was washed with 25.3 ml of heptane. The filtrate was separated to obtain a layer of heptane. To the resulting heptane layer, 12.1 ml of heptane was added, and the heptane layer was separated and washed with 12.1 ml of DMF. To the resulting heptane layer, 12.1 ml of heptane was added, and the heptane layer was washed once with 12.1 ml of 1N hydrochloric acid, once with 12.1 ml of a 5% aqueous solution. % hydrogen carbonate and once with 12.1 ml of water. To the resulting heptane layer, 12.1 ml of heptane was added, and the heptane layer was separated and washed twice with 12.1 ml of acetonitrile. The heptane layer was concentrated under reduced pressure, and a resulting residue was purified by silica gel column chromatography (heptane: ethyl acetate = 80: 1 ^ 0: 100) to provide 1.29 g of TIPS2-Xtn- C = O (C8). 1H NMR (400 MHz, CDCls) 81.02-1.08 (m, 42H), 1.33-1.44 (m, 12H), 1.44-1.60 (m, 8H), 1.79 -1.89 (m, 4H), 3.68 (t, 4H), 4.06 (t, 4H), 6.83 (d, 2H), 6.91 (dd, 2H), 8.22 ( d, 2H) 13C NMR (100 MHz, CDCla) 812.2 (6C), 18.2 (12C), 25.9 (2C), 26.1 (2C), 29.1 (2C), 29.5 (4C), 33.1 (2C), 63.6 (2C), 68.8 (2C), 100.8 (2C), 113.3 (2C), 115.8 (2C), 128.2 ( 2C), 158.2 (2C), 164.4 (2C), 175.7 ESIMS MH + 797.5

Example (3-b)

In a mixed solution of 6.6 ml of THF (anhydrous) and 0.66 ml of methanol, 0.73 g (0.91 mmol) of TIPS2-Xtn-C = O (Cs) were dissolved and 0, 28 g (7.30 mmol) of sodium borohydride to the mixed solution. The solution was heated to 35 ° C and stirred for 10 minutes. To the solution, 0.66 ml of methanol was added and the solution was stirred at 35 ° C for 50 minutes. Furthermore, 0.14 g (3.65 mmol) of sodium borohydride and 0.66 ml of methanol were added to the solution, and the solution was stirred at 35 ° C for 18 hours and 30 minutes. Furthermore, 16.4 ml of acetone and 66.3 ml of hexane were added to the solution, and the solution was washed four times with 36.5 ml of a 5% aqueous sodium hydrogen carbonate solution. To a resulting heptane layer, 3.3 ml of hexane and 5.1 g of anhydrous sodium sulfate were added and the hexane layer was stirred thoroughly and then filtered. The filtration residue was washed with 3.3 ml of hexane and the filtrate was concentrated under reduced pressure to provide 0.72 g of TIPS2-Xtn-OH (Cs).

1H NMR (400 MHz, Benzene ^) 8 1.12-1.16 (m, 42H), 1.22-1.37 (m, 12H), 1.37-1.45 (m, 4H), 1 , 52-1.66 (m, 9H), 3.67 (t, 8H), 5.57 (d, 1H), 6.76 (dd, 2H), 6.85 (d, 2H), 7, 40 (d, 2H)

13C NMR (100 MHz, Benzene ^) 812.8 (6C), 18.7 (12C), 26.6 (2C), 26.7 (2C), 29.9 (2C), 30.1 (2C) , 30.2 (2C), 33.8 (2C), 63.4, 64.1 (2C), 68.5 (2C), 102.0 (2C), 111.9 (2C), 116.8 (2C), 131.5 (2C), 152.5 (2C), 160.9 (2C)

ESIMS MNa + 821.5

Example 4

Synthesis of TBDPS2-Xtn-OH

(Hereinafter, Br- (CH2) n-OTBDPS, TBDPS2-Xtn-C = O and TBDPS2-Xtn-OH represent the structures in the drawing).

Example (4-a)

1.16 g (2.38 mmol) of Br- (CH2) ii-OTBDPS, 0.24 g (1.06 mmol) of 3,6-dihydroxyxanthone and 0.53 g (3.80 mmol) of potassium carbonate they were suspended in 7.0 ml of DMF, heated to 85 ° C and stirred for 3 hours. The reaction solution was filtered and the filtration residue was washed with 14.8 ml of heptane. The filtrate was separated to obtain a layer of heptane. 7.0 ml of heptane was added to the resulting heptane layer, and the heptane layer was separated and washed with 7.0 ml of acetonitrile. To the resulting heptane layer, 7.0 ml of heptane was added, and the heptane layer was washed once with 7.0 ml of 1N hydrochloric acid, once with 7.0 ml of a 5-strength aqueous solution. % hydrogen carbonate and once with 7.0 ml of water. To the resulting heptane layer, 7.0 ml of heptane was added, and the heptane layer was separated and washed twice with 7.0 ml of acetonitrile. The heptane layer was concentrated under reduced pressure, and a resulting residue was purified by silica gel column chromatography (heptane: ethyl acetate = 80: 1 ^ 0: 100) to provide 0.67 g of TBDPS2-Xtn- C = O.

1H NMR (400 MHz, CDCls) 8 1.05 (s, 18H), 1.24-1.42 (m, 24H), 1.42-1.63 (m, 8H), 1.77-1, 89 (m, 4H), 3.66 (t, 4H), 4.07 (t, 4H), 6.84 (d, 2H), 6.92 (dd, 2H), 7.3 0-7, 44 (m, 12H), 7.60-7.70 (m, 8H), 8.23 (d, 2H) 13C NMR (100 MHz, CDCla) 8 19.4 (2C), 25.9 (2C) , 26.1 (2C), 27.0 (6C), 29.2-29.7 (12C), 32.7 (2C), 64.2 (2C), 68.8 (2C), 100, 8 (2C), 113.4 (2C), 11 5.8 (2C), 127.7 (8C), 128.3 (2C), 129.6 (4C), 134.3 (4C), 135, 7 (8C), 158.2 (2C), 164.4 (2C), 175.7 ESIMS MNa + 1067.5

Example (4-b)

In a mixed solution of 2.3 ml of THF (anhydrous) and 0.23 ml of methanol, 0.33 g (0.32 mmol) of TBDPS2-Xtn-C = O were dissolved and 95 mg (2, 52 mmol) of sodium borohydride to the mixed solution. The solution was heated to 35 ° C and stirred for 10 minutes. To the solution, 0.23 ml of methanol was added and the solution was stirred at 35 ° C for 50 minutes. In addition, 48 mg (1.26 mmol) of sodium borohydride and 0.23 ml of methanol were added to the solution, and the solution was stirred at 35 ° C for 18 hours and 30 minutes, then cooled to room temperature and stirred for 49 hours and 30 minutes. Furthermore, 5.7 ml of acetone and 22.9 ml of hexane were added to the solution, and the solution was washed four times with 12.6 ml of a 5% aqueous sodium hydrogen carbonate solution. To a resulting heptane layer, 1.2 ml of hexane and 2.3 g of anhydrous sodium sulfate were added and the hexane layer was thoroughly stirred and then filtered. The filtration residue was washed with 1.2 ml of hexane and the filtrate was concentrated under reduced pressure to provide 0.31 g of TBDPS2-Xtn-OH.

1H NMR (400 MHz, Benzene ^) 8 1.20 (s, 18H), 1.22-1.29 (m, 24H), 1.31-1.43 (m, 4H), 1.53-1 , 69 (m, 9H), 3.65-3.73 (m, 8H), 5.57 (d, 1H), 6.77 (dd, 2H), 6.85 (d, 2H), 7, 21-7.27 (m, 12H), 7.40 (d, 2H), 7.77-7.83 (m, 8H)

ESIMS MNa + 1069.2

Example 5

Synthesis of TIPS2-Xtn-OH (C14)

(Hereinafter, Br- (CH2) 14-OTIPS, TIPS2-Xtn-C = O (C14) and TIPS2-Xtn-OH (C14) represent the structures in the drawing).

Example (5-a)

1.53 g (3.34 mmol) of Br- (CH2) 14-OTIPS, 0.34 g (1.51 mmol) of 3,6-dihydroxyxanthone and 0.75 g (5.43 mmol) of potassium carbonate they were suspended in 10.1 ml of DMF, heated to 85 ° C and stirred for 3 hours. The reaction solution was filtered and the filtration residue was washed with 21.1 ml of heptane. The filtrate was separated to obtain a layer of heptane. 10.1 ml of heptane was added to the resulting heptane layer, and the heptane layer was separated and washed with 10.1 ml of DMF. To the resulting heptane layer, 10.1 ml of heptane was added, and the heptane layer was washed once with 10.1 ml of 1N hydrochloric acid, once with 10.1 ml of a 5% aqueous solution. % hydrogen carbonate and once with 10.1 ml of water. To the resulting heptane layer, 10.1 ml of heptane was added, and the heptane layer was separated and washed twice with 10.1 ml of acetonitrile. The heptane layer was concentrated under reduced pressure to provide 1.34 g of TIPS2-Xtn-C = O (C14).

1H NMR (400 MHz, CDCh) 81.04-1.08 (m, 42H), 1.23-1.42 (m, 40H), 1.43-1.58 (m, 4H), 1.79 -1.89 (m, 4H), 3.66 (t, 4H), 4.06 (t, 4H), 6.83 (d, 2H), 6.91 (dd, 2H), 8.22 ( d, 2H)

ESIMS MH + 965.8

Example (5-b)

TIPS2-Xtn-OH (Ci4) was obtained in a similar manner to TIPS2-Xtn-OH (C8).

1H NMR (400 MHz, Benzene-da) 8 1.12-1.16 (m, 42H), 1.23-1.49 (m, 40H), 1.57-1.69 (m, 9H), 3.66-3.73 (m, 8H), 5.57 (d, 1H), 6.77 (dd, 2H), 6.86 (d, 2H), 7.40 (d, 2H)

ESIMS MNa + 990.2

Example 6

Synthesis of TIPS2-Xtn-OH (C8OC2)

(Hereinafter, Br- (CH2) 8-O- (CH2) 2-OTIPS, TIPS2-Xtn-C = O (C8OC2) and TIPS2-Xtn-OH (C8OC2) represent the structures in the drawing. ).

Example (6-a)

0.95 g (2.31 mmol) of Br- (CH2) 8-O- (CH2) 2-OTIPS, 0.23 g (1.03 mmol) of 3,6-dihydroxyxanthone and 0.57 g (4 , 11 mmol) of potassium carbonate were suspended in 6.8 ml of DMF, heated to 85 ° C and stirred for 2 hours and 40 minutes. The reaction solution was filtered and the filtration residue was washed with 14.4 ml of heptane. The filtrate was separated to obtain a layer of heptane. 6.8 ml of heptane was added to the resulting heptane layer. The heptane layer was separated and washed with 6.8 ml of DMF. To the resulting heptane layer, 6.8 ml of heptane was added, and the heptane layer was washed once with 6.8 ml of 1N hydrochloric acid, once with 6.8 ml of a 5% aqueous solution. % hydrogen carbonate and once with 6.8 ml of water. To the resulting heptane layer, 6.8 ml of heptane was added, and the heptane layer was separated and washed with 6.8 ml of acetonitrile. The heptane layer was separated and washed once more with the heptane and acetonitrile, and then the heptane layer was concentrated under reduced pressure. A resulting residue was purified by silica gel column chromatography (heptane: ethyl acetate = 40: 1 ^ 0: 100) to yield 0.24 g of TIPS2-Xtn-C = O (CsOC2).

1H NMR (400 MHz, CDCla) 81.03-1.07 (m, 42H), 1.25-1.43 (m, 12H), 1.43-1.53 (m, 4H), 1.53 -1.62 (m, 4H), 1.77-1.89 (m, 4H), 3.48 (t, 4H), 3.52 (t, 4H), 3.83 (t, 4H), 4.06 (t, 4H), 6.82 (d, 2H), 6.91 (dd, 2H), 8.21 (d, 2H)

ESIMS MH + 885.6

Example (6-b)

TIPS2-Xtn-OH (CsOC2) was obtained in a similar manner to TIPS2-Xtn-OH (Cs).

1H NMR (400 MHz, Benzene ^) 81.11-1.15 (m, 42H), 1.20-1.29 (m, 8H), 1.29-1.42 (m, 8H), 1, 54-1.66 (m, 9H), 3.39 (t, 4H), 3.49 (t, 4H), 3.68 (t, 4H), 3.83 (t, 4H), 5.58 (d, 1H), 6.76 (dd, 2H), 6.85 (d, 2H), 7.41 (d, 2H)

ESIMS MNa + 909.8

Example 7

Synthesis of TIPS2-Xtn-OH (C10-CONH-C2)

(Hereinafter, Br- (CH2) io-CONH- (CH2) 2-OTIPS, TIPS2-Xtn-C = O (Cio-CONH-C2) and TlPS2-Xtn-OH (Cio-CONH- C2) represent the structures in the drawing).

Example (7-a)

1.63 g (3.50 mmol) of Br- (CH2) 10-CONH- (CH2) 2-OTIPS, 0.29 g (1.25 mmol) of 3,6-dihydroxyxanthone and 0.69 g (5 0.00 mmol) of potassium carbonate were suspended in 8.3 ml of DMF, heated to 115 ° C and stirred for 2 hours. The reaction solution was filtered. To a filtrate, 25 ml of water was added to subject it to suspension washing, and a precipitate was collected by filtration. The suspension was washed with water and filtration was carried out once more. To the resulting precipitate, 25 ml of acetonitrile was added for suspension washing, and a precipitate was collected by filtration. Acetonitrile suspension washing and filtration were carried out once more. The resulting precipitate was dried under reduced pressure to obtain 0.99 g of TIPS2-Xtn-C = O (C10-CONH-C2).

1H NMR (400 MHz, CDCla) 8 1.03-1.08 (m, 42H), 1.25-1.42 (m, 20H), 1.43-1.53 (m, 4H), 1, 56-1.68 (m, 4H), 1.79 1.88 (m, 4H), 2.18 (t, 4H), 3.40 (q, 4H), 3.76 (t, 4H), 4.06 (t, 4H), 5.89 (t, 2H), 6.83 (d, 2H), 6.91 (dd, 2H), 8.21 (d, 2H) ESIMS MNa + 1017.7

Example (7-b)

In a mixed solution of 1.5 ml of THF (anhydrous) and 0.15 ml of methanol, 0.21 g (0.21 mmol) of TIPS2-Xtn-C = O (C10-CONH-C2) and 64 mg (1.69 mmol) of sodium borohydride was added to the mixed solution. The solution was heated to 35 ° C and stirred for 10 minutes. To the solution, 0.15 ml of methanol was added and the solution was stirred at 35 ° C for 50 minutes. Furthermore, 32 mg (0.84 mmol) of sodium borohydride and 0.15 ml of methanol were added to the solution and the solution was stirred at 35 ° C for 21 hours and 10 minutes. Furthermore, 3.8 ml of acetone and 15.3 ml of ethyl acetate were added to the solution, and the solution was washed four times with 8.4 ml of a 5% aqueous sodium hydrogen carbonate solution. To an organic layer, 0.8 ml of ethyl acetate and 1.47 g of anhydrous sodium sulfate were added, and the organic layer was thoroughly stirred and then filtered. The filtration residue was washed with 0.8 ml of ethyl acetate and the filtrate was concentrated under reduced pressure to provide 0.21 g of TIPS2-Xtn-OH (C10-CONH-C2).

ESIMS MNa + 1019.6

Example 8

Synthesis of TIPS3-Xtn-NH2

(Hereinafter, Br- (CH2) 10-CONH-C (CH2OTIPS) 3, TIPS3-Xtn-C = O, TIPS3-Xtn-OH, TlPS3-Xtn-NHFmoc and TIPS3-Xtn-NH2 represent structures in the drawing).

Example (8-a)

9.01 g (10.8 mmol) of Br- (CH2) 10-CONH-C (CH2OTIPS) 3, 2.86 g (12.9 mmol) of 3-hydroxanthene-9-one and 2.69 g ( 19.4 mmol) of potassium carbonate were suspended in 72 ml of DMF, heated to 120 ° C and stirred for 5 hours. The reaction solution was filtered and the filtration residue was washed with 151 ml of heptane. The filtrate was separated to obtain a layer of heptane. To the resulting heptane layer, 72 ml of heptane was added. The heptane layer was separated and washed with 72 ml of DMF. Furthermore, 72 ml of DMF was added to the heptane layer and the heptane layer was separated and washed twice. The resulting heptane layer was washed once with 72 ml of water. The heptane layer was concentrated under reduced pressure to provide 5.68 g of TIPS3-Xtn-C = O.

1H NMR (400MHz, CDCb) 1NMR (400MHz, CDCb) 51.02-1.08 (m, 63H), 1.24-1.39 (m, 10H), 1.44-1.62 (m, 4H), 1.85 (quin., 2H), 2.09 (t, 2H), 4.04 (s, 6H), 4.08 (t, 2H), 5.75 (s, 1H ), 6.87 (d, 1H), 6.94 (dd, 1H), 7.37 (t, 1H), 7.45 (d, 1H), 7.66-7.72 (m, 1H) , 8.24 (d, 1H), 8.33 (dd, 1H)

Example (8-b)

In a mixed solution of 4.0 ml of THF (anhydrous) and 0.8 ml of methanol, 0.70 g (0.73 mmol) of TIPS3-Xtn-C = O were dissolved and 0.22 g ( 5.81 mmol) of sodium borohydride to the mixed solution. The solution was heated to 35 ° C and stirred for 4 hours. The reaction was quenched with 0.86 ml of acetone and the solution was concentrated under reduced pressure. A resulting residue was dissolved in 13 ml of toluene, and the residue was washed twice with 3.9 ml of a 5% aqueous sodium hydrogen carbonate solution and twice with 3.9 ml of water to provide a toluene solution which contained TIPS3-Xtn-OH.

Example (8-c)

To the toluene solution obtained in the previous step, 0.21 g (0.87 mmol) of 9-fluorenylmethyl carbamate, 0.42 ml of acetic acid and 1.72 g of 4A molecular sieves were added and the Solution was stirred at 50 ° C for 3 hours and 30 minutes. The reaction solution was filtered, diluted with 10 ml of toluene and washed once more with 40 ml of a 5% aqueous solution of sodium hydrogen carbonate, once with 30 ml of 5% aqueous sodium hydrogen carbonate and once with 20 ml of water. The solution was concentrated under reduced pressure to provide a mixture containing TIPS3-Xtn-NHFmoc.

Example (8-d)

The mixture obtained in the previous step was dissolved in 6.9 ml of THF, and 0.15 ml (1.03 mmol) of DBU was added to the mixture and the mixture was stirred at room temperature for 1 hour. The solution was concentrated under reduced pressure, and a residue was dissolved in 21.0 ml of heptane, and separated and washed with 7.0 ml of DMF. To a resulting heptane layer, 7.0 ml of heptane was added. The heptane layer was separated and washed twice with 7.0 ml of DMF. To the heptane layer, 7.0 ml of heptane was added and the heptane layer was separated and washed with 7.0 ml of 50% aqueous acetonitrile. The heptane layer was separated and washed with the heptane and 50% aqueous acetonitrile once more. To the resulting heptane layer, 7.0 ml of heptane was added, and the heptane layer was separated and washed with 7.0 ml of acetonitrile. After separating and washing the heptane layer once more with the heptane and acetonitrile, the heptane layer was concentrated under reduced pressure and the resulting residue was purified by column chromatography on silica gel (heptane: ethyl acetate: triethylamine = 17.8: 1.2: 1 ^ 0: 19: 1) to provide 0.44 g of TIPS3-Xtn-NH2.

1H NMR (400 MHz, Benzene-da) 8 1.14-1.18 (m, 63H) 1.22-1.40 (m, 14H), 1.63 (quin., 2H), 1.75 ( quin., 2H), 2.20 (t, 2H), 3.69 (t, 2H), 4.43 (s, 6H), 4.70 (s, 1H), 5.91 (s, 1H) , 6.78 (dd, 1H), 6.82 (d, 1H), 6.93 (td, 1H), 7.04 (td, 1H), 7.14 (dd, 1H), 7.22 ( d, 1H), 7.28 (dd, 1H)

Example 9

Synthesis of TIPS3-Xtn-OH (6-OMe)

(Hereinafter TIPS3-Xtn-C = O (6-OMe) and TIPS3-Xtn-OH (6-OMe) represent the structures in the drawing).

Example (9-a)

0.40 g (0.48 mmol) of Br- (CH2) 10-CONH-C (CH2OTI PS) 3, 0.22 g (0.91 mmol) of 3-hydroxy-6-methoxyxanthone and 0.20 g (1.43 mmol) of potassium carbonate were suspended in 3.2 ml of DMF, heated to 115 ° C and stirred for 3 hours and 20 minutes. The reaction solution was filtered and the filtration residue was washed with 4.8 ml of heptane. The filtrate was separated to obtain a layer of heptane. 2.4 ml of heptane was added to the resulting heptane layer, and the heptane layer was separated and washed with 2.4 ml of DMF. To the resulting heptane layer, 2.4 ml of heptane was added, and the heptane layer was washed once with 2.4 ml of 1N hydrochloric acid, once with 2.4 ml of a 5-mL aqueous solution. % hydrogen carbonate and once with 2.4 ml of water. To the resulting heptane layer, 2.4 ml of heptane was added, and the heptane layer was separated and washed with 2.4 ml of acetonitrile. The heptane layer was separated and washed once more with the heptane and acetonitrile, and then the heptane layer was concentrated under reduced pressure to provide 0.27 g of TlPS3-Xtn-C = O (6-OMe) .

1H NMR (400 MHz, CDCla) 81.00-1.07 (m, 63H), 1.20-1.40 (m, 10H), 1.48 (quin., 2H), 1.57 (quin. , 2H), 1.84 (quin., 2H), 2.09 (t, 2H), 3.92 (s, 3H), 4.02-4.09 (m, 8H), 5.75 (s , 1H), 6.84 (dd, 2H), 6.89-6.94 (m, 2H), 8.20-8.25 (m, 2H) ESIMS MH + 998.8

Example (9-b)

TIPS3-Xtn-OH (6-OMe) was obtained in a similar manner to TIPS2-Xtn-OH (Cs).

1H NMR (400 MHz, Benzene ^) 8 1.15-1.19 (m, 63H), 1.20-1.41 (m, 12H), 1.55-1.80 (m, 5H), 2 , 19 (t, 2H), 3.30 (s, 3H), 3.70 (t, 2H), 4.42 (s, 6H), 5.56 (d, 1H), 5.91 (s, 1H), 6.68 (dd, 1H), 6.75-6.80 (m, 2H), 6.85 (d, 1H), 7.36-7.43 (m, 2H) ESIMS MNa + 1022, 7

Example 10

Synthesis of TIPS4-Xtn-OH (C-i0-CONH-CH (CH2) 2)

(Hereinafter, Br- (CH2) io-CONH-CH (CH2-OTIPS) 2, TIPS4-Xtn-C = O (C10-CONH-CH (CH2) 2) and TIPS4-Xtn-oH (Cio-CONH-CH (CH2) 2) represent the structures in the drawing).

Example (10-a)

1.53 g (2.35 mmol) of Br- (CH2> 10-CONH-CH (CH2-OTIPS) 2, 0.19 g (0.84 mmol) of 3,6-dihydroxyxanthone and 0.47 g ( 3.36 mmol) of potassium carbonate were suspended in 5.6 ml of DMF, heated to 115 ° C and stirred for 3 hours and 30 minutes The reaction solution was filtered and the filtration residue was washed with 11, 8 ml of heptane The filtrate was separated to obtain a heptane layer 5.6 ml of heptane was added to the resulting heptane layer, and the heptane layer was separated and washed with 5.6 ml of DMF. To the resulting heptane layer, 5.6 ml of heptane was added, and the heptane layer was washed once with 5.6 ml of 1N hydrochloric acid, once with 5.6 ml of a 5% aqueous solution. % hydrogen carbonate and once with 5.6 ml of water To the resulting heptane layer, 5.6 ml of heptane was added, and the heptane layer was separated and washed with 5.6 ml of acetonitrile. The heptane layer was separated and washed once more with the heptane and acetonitrile. The heptane layer was concentrated under reduced pressure to provide 0.74 g of TIPS4-Xtn-C = O (C10-CONH-CH (CH2) 2).

1H NMR (400 MHz, CDCla) 81.04-1.08 (m, 84H), 1.22-1.42 (m, 20H), 1.43-1.52 (m, 4H), 1.56 -1.66 (m, 4H), 1.79-1.88 (m, 4H), 2.16 (t, 4H), 3.64-3.70 (m, 4H), 3.86-3 , 91 (m, 4H), 3.94-4.04 (m, 2H), 4.06 (t, 4H), 5.84 (d, 2H), 6.83 (d, 2H), 6, 91 (dd, 2H), 8.22 (d, 2H)

ESIMS MH + 1367.9

Example (10-b)

TIPS4-Xtn-OH (C10-CONH-CH (CH2) 2) was obtained in a similar manner to TIPS2-Xtn-OH (Cs).

1H NMR (400 MHz, Benzene ^) 81.10-1.15 (m, 84H), 1.20-1.41 (m, 24H), 1.60-1.73 (m, 9H), 2, 03 (t, 4H), 3.68-3.77 (m, 8H), 4.01-4.07 (m, 4H), 4.27-4.36 (m, 2H), 5.61 ( d, 1H), 5.71 (d, 2H), 6.78 (dd, 2H), 6.87 (d, 2H), 7.44 (d, 2H) ESIMS MNa + 1391.7

Example 11

Synthesis of TIPS6-Xtn-NH2

(Hereinafter TIPS6-Xtn-C = O, TIPS6-Xtn-OH, TIPS6-Xtn-NHFmoc and TIPS6-Xtn-NH2 represent the structures in the drawing).

Example (11-a)

8.18 g (9.77 mmol) of Br- (CH2) 10-CONH-C (CH2OTIPS) 3, 0.68 g (3.00 mmol) of 3,6-dihydroxyxanthone and 1.50 g (10, 9 mmol) of potassium carbonate were suspended in 20.0 ml of DMF, heated to 90 ° C and stirred for 9.5 hours. The reaction solution was filtered and the filtration residue was washed with 42 ml of heptane. The filtrate was separated to obtain a layer of heptane. To the resulting heptane layer, 20 ml of heptane was added. The heptane layer was separated and washed with 20 ml of DMF. The heptane layer was separated and washed with the heptane and DMF once more. To the resulting heptane layer, 20 ml of heptane was added, and the heptane layer was washed once with 20 ml of 1N hydrochloric acid, once with 20 ml of a 5% aqueous hydrogen carbonate solution, and twice with 20 ml of water. 20 ml of heptane was added to the resulting heptane layer, and the heptane layer was separated and washed once with 20 ml of DMF and twice with 20 ml of acetonitrile. The heptane layer was concentrated under reduced pressure, and a resulting residue was purified by silica gel column chromatography (heptane: ethyl acetate = 35: 1 ^ 10: 1) to provide 4.13 g of TIPS6-Xtn- C = O.

1H NMR (400 MHz, Chloroform-d-,) 8 1.00-1.12 (m, 126H), 1.25-1.37 (m, 20H), 1.47 (quint., 4H), 1 , 57 (quint., 4H), 1.83 (quint., 4H), 2.08 (t, 4H), 4.03 (s, 12H), 4.05 (t, 4H), 5.74 ( s, 2H), 6.82 (dd, 2H), 6.88-6.92 (m, 2H), 8.21 (dd, 2H) Example (11-b)

In a mixed solution of 12.5 ml of THF (anhydrous) and 3.8 ml of methanol, 3.00 g (1.72 mmol) of TIPS6-Xtn-C = O were dissolved and 0.79 g ( 20.8 mmol) of sodium borohydride to the mixed solution. The solution was stirred at room temperature for 15 hours. The reaction was quenched with 47.0 ml of acetone and the solution was concentrated under reduced pressure. A resulting residue was dissolved in 37.6 ml of toluene and washed with 25.1 ml of a 5% aqueous sodium hydrogencarbonate solution. Furthermore, the residue was washed three times with 25.1 ml of the 5% aqueous sodium hydrogencarbonate solution to provide a toluene solution of a mixture containing TIPS 6-Xtn-OH.

1H NMR (400 MHz, Benzene ^) 8 1.07-1.13 (m, 126H), 1.14-1.26 (m, 20H), 1.34-1.37 (m, 4H), 1 , 58 (quint., 4H), 1.68 (quint., 4H), 2.13 (t, 4H), 3.64 (t, 4H), 4.36 (s, 12H), 5.52-5, 55 (d, 1H), 5.85 (s, 2H), 6.72 (dd, 2H), 6.80 (d, 2H), 7.37 (d, 2H)

Example (11 -c)

To the toluene solution obtained in the previous step, 0.50 g (2.10 mmol) of 9-fluorenylmethyl carbamate, 5.74 ml of acetic acid and 0.49 g of 4 A molecular sieves were added and the solution was stirred at room temperature for 6 hours. After cooling the reaction solution to 5 ° C, 45.1 ml of a saturated aqueous sodium hydrogen carbonate solution was added to the solution and the solution was stirred for 30 minutes. The reaction solution was filtered and the filtration residue was washed with 13.5 ml of toluene and separated. The filtrate was then washed once with 45.1 ml of a saturated aqueous solution of sodium hydrogencarbonate, once with 45.1 ml of a 5% aqueous solution of sodium hydrogencarbonate and twice with 45.1 ml of water. An organic layer was concentrated under reduced pressure to provide a mixture containing TIPS2-Xtn-NHFmoc.

Example (11-d)

The mixture obtained in the previous step was dissolved in 12.7 ml of THF, and 0.69 ml (4.58 mmol) of DBU was added to the mixture and the mixture was stirred at room temperature for 1 hour. The reaction solution was cooled to 5 ° C, the reaction was quenched with 3.1 ml of 1N hydrochloric acid, and the solution was concentrated under reduced pressure. A resulting residue was dissolved in 25.5 ml of heptane and the solution was washed six times with 25.5 ml of acetonitrile. A layer of heptane was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (heptane: ethyl acetate: triethylamine = 18.75: 1.25: 1 ^ 0: 19: 1) to provide 1.37 g of TIPS6-Xtn-NH2.

1H NMR (400 MHz, Benzene ^) 8 1.06-1.14 (m, 126H), 1.14-1.19 (m, 20H), 1.25-1.32 (m, 4H), 1 , 58 (quint., 4H), 1.69 (quint., 4H), 2.13 (t, 4H), 3.65 (t, 4H), 4.37 (s, 12H), 4.69 (s, 1H), 5.84 (s, 2H), 6.73 (dd, 2H), 6.81 (d, 2H), 7.19 (d, 2H)

Example 12

Synthesis and deprotection of Fmoc-Cys (TIPS2-Xtn) -NH2

(Hereinafter, Fmoc-L-Cys-NH2 and Fmoc-Cys (TIPS2-Xtn) -NH2 represent the structures in the drawing).

Example (12-a)

In a mixed solution of 0.83 ml of THF (anhydrous) and 83 µl of methanol, 0.10 g (0.12 mmol) of TIPS2-Xtn-C = O were dissolved and 35 mg (0.92 mmol ) of sodium borohydride to the mixed solution. The solution was heated to 35 ° C and stirred for 10 minutes. To the solution, 83 µl of methanol was further added and stirred at 35 ° C for 50 minutes. Furthermore, 17 mg (0.46 mmol) of sodium borohydride and 83 µl of methanol were added to the solution and the solution was stirred at 35 ° C for 20 hours and 45 minutes. Furthermore, 2.0 ml of acetone was added to the solution, and the reaction solution was concentrated under reduced pressure. A resulting residue was dissolved in 2.5 ml of toluene and washed 4 times with 1.7 ml of a 5% aqueous sodium hydrogencarbonate solution. A resulting organic layer was diluted with 0.1 ml of toluene and 0.71 g of anhydrous sodium sulfate was added to the organic layer. The organic layer was thoroughly stirred and filtered and the filtration residue was washed with 0.4 ml of toluene to provide a toluene solution containing TIPS2-Xtn-OH.

Example (12-b)

To the toluene solution obtained in the previous step, 43 mg (0.13 mmol) of Fmoc-L-Csy-NH2, 39 mg of 4 A molecular sieves and 0.38 ml of acetic acid were added and the solution stirred at 25 ° C for 1 hour and 30 minutes. After the reaction solution was cooled to 5 ° C, and the reaction was quenched with 4.5 ml of a saturated aqueous sodium hydrogen carbonate solution. To the solution, 3.0 ml of toluene was added, and the solution was washed twice with 4.5 ml of an aqueous sodium hydrogencarbonate solution and once with 3.0 ml of water. An organic layer was concentrated under reduced pressure.

To a resulting residue, 3.1 ml of methanol was added, and the residue was cooled to 5 ° C and subjected to suspension washing, and a precipitate was collected by filtration. The suspension was washed with methanol and the filtration was repeated twice. The resulting precipitate was dissolved in a mixed solvent including 30 ml of heptane and 4.5 ml of CPME, and the resultant was washed three times with 30 ml of acetonitrile. A layer of heptane was concentrated under reduced pressure to provide 76 mg of Fmoc-Cys (TIPS2-Xtn) -NH2. ESIMS MNa + 1229.8

Example (12-c)

57 mg (0.05 mmol) of Fmoc-Cys (TIPS2-Xtn) -NH2 was dissolved in 0.76 ml of dichloromethane. To the solution, 47 µl (0.29 mmol) of 3,6-dioxa-1,8-octanedithiol, 47 µl (0.22 mmol) of triisopropylsilane and 94 µl (1.23 mmol) of trifluoroacetic acid were added. and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure and the residue was poured into 3.8 ml of diisopropyl ether cooled to 5 ° C, and a precipitate was collected by filtration. The suspension washing with the diisopropyl ether and the filtration were repeated three times, and the precipitate was collected by filtration. The precipitate was dried under reduced pressure to provide 9 mg of Fmoc-L-Cys-NH2. ESIMS MNa + 364.9

Example 13

Study on the increase in solubility with respect to peptide compounds

The solubility of a compound protected by the xanthene protective agent of the present invention was measured. Figure 1 shows the results.

Peptide used as a model: H-Phe-Leu-NH2

H-Phe-Leu-NH2 and H-Phe-Leu-NH- (TIPS2-Xtn) were synthesized, and each compound was saturated in cyclopentyl methyl ether (CPME) at 25 ° C to measure the solubility of each compound.

With respect to H-Phe-Leu-NH2 not bound to a TIPS-like protective agent, 0.5 mM of the peptide was dissolved in CPME. Compared to that case, when H-Phe-Leu-NH2 bound to TIPS2-Xtn-NH2, 586 mM of the peptide, which is approximately 1100 times or more the amount of the peptide in the first case, dissolved in CPMe, it which indicates that the latter case improved in solubility. The results are shown in Fig. 1. From these results, it was found that derivatization with the xanthene protective agent leads to a significant improvement in the solubility of the peptide. Herein, H-Phe-Leu-NH2 and H-Phe-Leu-NH- (TIPS2-Xtn) have the following structures.

Example (13-a)

Synthesis of H-Phe-Leu-NH- (TIPS2-Xtn)

1.67 g (1.89 mmol) of TIPS2-Xtn-NH2 were dissolved in 18.9 ml of CPME. To the resultant, 8.1 ml of DMF, 1.32 ml (7.55 mmol) of DIPEA, 1.00 g (2.83 mmol) of Fmoc-Leu-OH, 0.40 g (2, 83 mmol) of ethyl cyano (hydroxyimino) acetate (Oxyma) and 1.21 g (2.83 mmol) of (1-cyano-2-ethoxy-2-oxoethylideneaminooxy) dimethylaminomorpholino-carbenium hexafluorophosphate (COMU) and the mixture stirred at room temperature for 50 minutes. After checking the disappearance of TIPS2-Xtn-NH2, 112 µl (1.13 mmol) of 2- (2-aminoethoxy) ethanol was added to the solution and the solution was stirred at room temperature for 15 minutes. To the reaction solution, 4.04 g (22.6 mmol) of sodium 3-mercapto-1-propanesulfonate dissolved in 18.9 ml of DMSO was added, and 1.9 ml of d Ms O and 2.12 ml (14.2 mmol) of DBU. Then the solution was stirred for 40 minutes. After checking the disappearance of Fmoc-Leu-NH- (TIPS2-Xtn) and after cooling the solution to 5 ° C, 3.72 ml (14.9 mmol) of 4 M CPME / HCl were added dropwise to the solution, and the solution was warmed to room temperature. Then, 0.8 ml of CPME, 80 ml of 20% aqueous sodium chloride solution and 68 ml of 10% aqueous sodium carbonate solution were added to the solution, and the solution was separated and washed. To the resulting organic layer, 0.6 ml of DMSO, 0.6 ml of DMF and 23 ml of a 50% aqueous dipotassium hydrogen phosphate solution were added and the solution was separated and washed to provide a mixed solution containing H-Leu-NH- (TIPS2-Xtn). Herein, Fmoc-Leu-NH- (TlPS2-Xtn) and H-Phe-Leu-NH- (TIPS2-Xtn) have the following structures.

To the resulting mixed solution, 3.4 ml of CPME, 11.3 ml of DMF, 1.31 ml (7.55 mmol) of DIPEA, 1.10 g (2.83 mmol) of Fmoc-Phe were added -OH, 0.40 g (2.83 mmol) of Oxyma and 1.21 g (2.83 mmol) of C ^or MU, and the solution was stirred at room temperature for 50 minutes. After checking the disappearance of H-Leu-NH- (TIPS2-Xtn), 112 µl (1.13 mmol) of 2- (2-aminoethoxy) ethanol was added to the solution and the solution was stirred at room temperature for 15 minutes. To the solution, 4.04 g (22.6 mmol) of sodium 3-mercapto-1-propanesulfonate dissolved in 18.9 ml of DMSO was added and the solution was cooled to 5 ° C. Then, 1.9 ml of DMSO and 2.12 ml (14.2 mmol) of DBU were added to the solution and the solution was stirred for 35 minutes. After checking the disappearance of Fmoc-Phe-Leu-NH- (TIPS2-Xtn), 3.72 ml (14.9 mmol) of CP ^m E 4 M / HCl were added dropwise to the solution and the solution was warmed to room temperature. Then 0.9 ml of CPME, 88 ml of 20% aqueous sodium chloride solution and 75 ml of 10% aqueous sodium carbonate solution were added to the solution, and the solution was separated and washed. To the resulting organic layer, 0.8 ml of DMSO, 0.8 ml of DMF and 31 ml of a 50% aqueous dipotassium hydrogen phosphate solution were added, and the solution was separated and washed. The solution was concentrated under reduced pressure, and a resulting residue was dissolved in 66 ml of heptane and separated and washed twice with 28 ml of acetonitrile. The heptane layer was concentrated under reduced pressure and a resulting residue was dried under reduced pressure to provide 1.75 g of H-Phe-Leu-NH- (TIPS2-Xtn).

ESIMS MNa + 1164.8

Herein, Fmoc-Phe-Leu-NH- (TIPS2-Xtn) has the following structure.

Example (13-b)

Synthesis of H-Phe-Leu-NH2

209 mg (0.18 mmol) of H-Phe-Leu-NH- (TIPS2-Xtn) were dissolved in 3.23 ml of dichloromethane. To the solution, 0.37 ml (5.10 mmol) of trifluoroethanol and 73 µl (0.96 mmol) of trifluoroacetic acid were added and the solution was stirred at room temperature for 1 hour and 10 minutes. After the disappearance of H-Phe-Leu-NH- (TIPS2-Xtn) was checked, the solution was concentrated under reduced pressure, and a residue was added dropwise to 18.8 ml of diisopropyl ether cooled to 5 ° C. The residue was then centrifuged at 3000 rpm for 4 minutes at 5 ° C, and a supernatant was removed by decantation, giving a precipitate. Diisopropyl ether suspension washing, centrifugation and decantation were repeated three times to obtain a precipitate. The precipitate was dried under reduced pressure to provide 49 mg of H-Phe-Leu-NH2.

ESIMS MH + 278.0

From the above results, it was found that a compound including a functional group protected by the xanthene protecting agent of the present invention has markedly improved solubility in an organic solvent.

Claims (12)

1. A xanthene compound of general Formula (1)

where Y is -OR17, R17 being a hydrogen atom, an active ester-carbonyl group or an active ester-sulfonyl group, -NHR18, R18 being a hydrogen atom or a linear or branched C1-C6 alkyl group or aralkyl group, an azide, a halogen atom, or a carbonyl oxygen = O; at least one of R1 to R8 is represented by Formula (2); -O-R9-X-A (2) and a residue is a hydrogen atom, a halogen atom, a C1-C4 alkyl group or a C1-C4 alkoxy group, wherein R9 is a linear or branched C1-C16 alkylene group; X is O or CONR19, where R19 is a hydrogen atom or a C1-C4 alkyl group; Y A is represented by the Formula (3), (4), (5), (6), (7), (8), (9), (10), (11), (12) or (13)

wherein R 10, R 11 and R 12, the same or different, are a linear or branched C1-C6 alkyl group or an aryl group optionally including a substituent; R13 is a single bond or a linear or branched C1-C3 alkylene group; Y R14, R15 and R16 are a linear or branched C1-C3 alkylene group. 2. The xanthene compound according to claim 1, wherein Y is -OR17, R17 being a hydrogen atom, an active ester-carbonyl group or an active ester-sulfonyl group, -NHR18, R18 being a hydrogen atom or a linear or branched C1-C6 alkyl group or aralkyl group, an azide or a halogen atom. 3. The xanthene compound according to claim 1, wherein Y is -OR17, R17 being a hydrogen atom, an active ester-carbonyl group or an active ester-sulfonyl group, or -NHR18, R18 being a hydrogen atom hydrogen or a linear or branched C1-C6 alkyl group or aralkyl group. 4. The xanthene compound according to claim 1, wherein Y is -OR17, R17 being a hydrogen atom, -NHR18, R18 being a hydrogen atom or a carbonyl oxygen = O. 5. The xanthene compound according to claim 1, wherein Y is -OR17, R17 being a hydrogen atom, or -NHR18, R18 being a hydrogen atom. 6. The xanthene compound according to any one of claims 1 to 5, wherein at least one of R1 to R8 is a group represented by Formula (2), and a residue is a hydrogen atom, a C1 alkyl group -C4 or a C1-C4 alkoxy group. 7. The xanthene compound according to any one of claims 1 to 6, wherein R9 is a linear or branched C2-C16 alkylene group. 8. The xanthene compound according to any one of claims 1 to 7, wherein R9 is a linear or branched C6-C16 alkylene group. 9. The xanthene compound according to any one of claims 1 to 8, wherein R13 is a single bond or a methylene group, and R, R and R are a methylene group. 10. A protective agent for protecting a carboxy group, a hydroxy group, a diol group, an amino group, an amide group or a mercapto group, wherein the protective agent contains the xanthene compound according to a any of claims 1 to 9. 11. A method for producing a compound with a protective agent to protect a carboxy group, a hydroxy group, a diol group, an amino group, an amide group, or a mercapto group, wherein the protective agent contains the xanthene compound according to with any one of claims 1 to 9. 12. A method of producing a peptide with a protective agent to protect a carboxy group, a hydroxy group, a diol group, an amino group, an amide group, or a mercapto group, wherein the protective agent contains the xanthene compound according to with any one of claims 1 to 9.